DeCure for Hyperinsulinism due to glucokinase deficiency
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for hyperinsulinism due to glucokinase deficiency — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleHyperinsulinism due to glucokinase deficiency maps to a 1-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for hyperinsulinism due to glucokinase deficiency is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
glucokinase (GCK) — GCK is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet 2rdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 4DCH · 1.79 Å · ligand (2R)-3-cyclopentyl-2-[4-(methylsulfonyl)phenyl]-N-(1,3-thiazol-2-yl)propanamide (4DC). Experimental structure, not a prediction.
What the evidence adds up to
A 2009 study of three children with de novo glucokinase activating mutations found a spectrum of clinical severity that corresponded to enzyme kinetics. The relative activity indexes of the mutant enzymes ranged from 26 (ins454A) to 8.9 (W99L) to 3.1 (M197I), compared to 1.0 for wild type. Diazoxide was effective in the child with the M197I mutation, ineffective in the child with ins454A, and only partially effective in the child with W99L. The estimated thresholds for glucose-stimulated insulin release were 1.1 mmol/l for ins454A, 2.2 mmol/l for W99L, and 3.5 mmol/l for M197I, versus 5.0 mmol/l for wild type. The ins454A mutation also impaired allosteric responses to glucokinase regulatory protein and to the activator drug RO0281675, whereas the M197I mutation did not.
A 2024 case report described a 41-year-old mother and her 15-year-old daughter with a novel GCK variant, c.212T>C (p.Val71Ala). Their hypoglycaemia was not pronounced. The report also noted a variant of uncertain significance in the ABCC8 gene (c.1903G>A, p.Ala635Thr) that may have contributed to the disease course. A separate 2020 case report described a 3.5-year-old child with the same p.Val71Ala mutation, inherited from his mother. That child required a glucose infusion rate greater than 8–10 mg/kg/min to maintain normoglycaemia. In silico analysis assessed the pathogenicity of this variant as of uncertain significance.
The 2009 study concluded that responsiveness to diazoxide varies with genotype in glucokinase hyperinsulinism and that hypoglycaemia can be more difficult to control than previously believed. The 2020 report noted that GCK mutations produce varying phenotypic characteristics and diazoxide responsiveness depending on the mutation type. The 2024 report described the p.Val71Ala variant as causing mild disease, but the 2020 case showed a more severe presentation in a young child with the same variant.
What is still missing is a systematic genotype-phenotype correlation for the many rare GCK variants, prospective data on long-term outcomes including neurodevelopment, and a trial design that stratifies patients by mutation type to test whether any drug other than diazoxide can consistently control hypoglycaemia. No funding source for such a trial has been announced.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Diabetes · 2009 · 122 citations · open access
Extremes of Clinical and Enzymatic Phenotypes in Children With Hyperinsulinism Caused by Glucokinase Activating Mutations
AbstractOBJECTIVE: Heterozygous activating mutations of glucokinase have been reported to cause hypoglycemia attributable to hyperinsulinism in a limited number of families. We report three children with de novo glucokinase hyperinsulinism mutations who displayed a spectrum of clinical phenotypes corresponding to marked differences in enzyme kinetics. RESEARCH DESIGN AND METHODS: Mutations were directly sequenced, and mutants were expressed as glutathionyl S-transferase-glucokinase fusion proteins. Kinetic analysis of the enzymes included determinations of stability, activity index, the response to glucokinase activator drug, and the effect of glucokinase regulatory protein. RESULTS: Child 1 had an ins454A mutation, child 2 a W99L mutation, and child 3 an M197I mutation. Diazoxide treatment was effective in child 3 but ineffective in child 1 and only partially effective in child 2. Expression of the mutant glucokinase ins454A, W99L, and M197I enzymes revealed a continuum of high relative activity indexes in the three children (26, 8.9, and 3.1, respectively; wild type = 1.0). Allosteric responses to inhibition by glucokinase regulatory protein and activation by the drug RO0281675 were impaired by the ins454A but unaffected by the M197I mutation. Estimated thresholds for glucose-stimulated insulin release were more severely reduced by the ins454A than the M197I mutation and intermediate in the W99L mutation (1.1, 3.5, and 2.2 mmol/l, respectively; wild type = 5.0 mmol/l). CONCLUSIONS: These results confirm the potency of glucokinase as the pancreatic beta-cell glucose sensor, and they demonstrate that responsiveness to diazoxide varies with genotype in glucokinase hyperinsulinism resulting in hypoglycemia, which can be more difficult to control than previously believed.
JCEM Case Reports · 2024 · 1 citations · open access
Mild Congenital Hyperinsulinism Caused by Mutation in Human <i>Glucokinase</i> Gene
AbstractAbstract Congenital hyperinsulinism (CHI) is a rare hereditary disease characterized by the development of hypoglycemia in both infants and adult patients. CHI may be induced by activating mutations in the glucokinase (GCK) gene, which encodes the human glucokinase enzyme. This form of the disease is characterized by considerable phenotypic heterogeneity and may vary in severity of its course. We present a familial case report of mild CHI caused by a novel variant, c.212T &gt; C (p.Val71Ala), in the GCK gene in a 41-year-old mother and a 15-year-old daughter. The clinical picture of hypoglycemia in the patients was not pronounced, which makes this clinical case remarkable. Moreover, a variant of uncertain clinical significance, с.1903G &gt; A (p.Ala635Thr), in the ABCC8 gene was detected, which may also have contributed to the course of the disease in these patients.
Journal of Clinical Review & Case Reports · 2020 · 0 citations · open access
Congenital Hyperinsulinism Due to a Novel Activating Glucokinase Mutation: A Case Report and Literature Review
AbstractBackground: Congenital Hyperinsulinism (CHI) constitutes a major cause of persistent and recurrent hypoglycemia, especially in the neonatal period, showing notable phenotypical heterogeneity among affected subjects. Activating mutations of the Glucokinase gene (GCK) are responsible for mild forms of hypoglycemia, due to CHI, usually easily medically managed. Case report: We present a patient at the age of 3.5 years old investigated for persistent hypoglycemia. Laboratory evaluation showed hyperinsulinism during the hypoglycemic episode with a required glucose infusion rate greater than 8-10 mg/kg/min to maintain normoglycemia. Targeted gene panel sequencing revealed an activating missense novel mutation p.Val71Ala in exon 3 of GCK gene, dominantly inherited by his mother. In silico, analysis of this novel missense variant assessed its pathogenicity as being of uncertain significance Conclusions: GCK gene mutations result in varying phenotypic characteristics and responsiveness to diazoxide depending on the type of activating mutation.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
